Project Abstract Glaucoma is the second leading cause of blindness worldwide, and current therapies are not always effective. Glaucoma is characterized by degeneration of retinal ganglion cells (RGC). RGCs carry vision information from the eye to the brain via axons that form the optic nerve (ON) as they exit the eye through the optic nerve head (ONH). Elevated intraocular pressure (IOP) is a key risk factor in glaucoma, and previous studies have shown that it increases biomechanical stress and strain in the ONH; further, the ONH is a primary region of damage in glaucoma. This and other evidence has led to the well-accepted hypothesis that biomechanical insult is a key driver leading to RGC death in glaucoma. However, a gap in current knowledge exists: the mechanisms by which biomechanical insult leads to RGC death are not well-understood. We can address this gap by comparing a regional biomechanical characterization of the ONH with a characterization of regional RGC death and cellular response patterns, such as astrocyte activation. Such a comparison will suggest critical levels of biomechanical insult leading to RGC loss and thus ultimately suggest targets for novel, non-IOP lowering therapies. Towards this end, experimental rodent glaucoma models, like the rat, are necessary for investigating cellular behavior since they allow for high subject numbers. However, there are substantial differences between rat and human ONH anatomy that likely result in different ONH biomechanical patterns between the species. Further, although rats with ocular hypertension undergo similar ONH pathophysiology to that in human glaucoma, they also exhibit a regional RGC death pattern where axons in the superior ON die first. Our central hypothesis is that the documented differences in the rat vs. human ONH anatomy are influential on rat ONH biomechanics, and that the regionalized rat RGC death and cell response patterns are a result of the biomechanical environment in the rat ONH. At least two characterizations of the rat ONH under elevated IOP are necessary to test this hypothesis: 1) biomechanical stress and strain patterns and 2) cellular response patterns. In this proposal, we plan to provide the biomechanical characterization through a combination of experimental and numerical methods. In Aim 1, we will determine the material properties of rat ONH tissues. Next, we will use a numerical method called finite element (FE) modeling to simulate stress and strain patterns in the rat ONH under elevated IOP. First, in Aim 2, we will conduct a sensitivity analysis using a generic rat ONH FE model to determine the sensitivity of rat ONH strains to different geometric and material parameters. We hypothesize that aspects of rat ONH anatomy that differ from human ONH anatomy will be highly influential on rat ONH biomechanics. Finally, in Aim 3, we will build 8 FE models that incorporate individual-specific rat ONH geometries, resulting in higher fidelity than in Aim 2. We hypothesize that regional strain patterns seen in our models will correlate with patterns of RGC death and cellular response seen in rat glaucoma studies. These comparisons will improve understanding of how biomechanical insult leads to RGC death in glaucoma, driving development of novel glaucoma therapies.